Pharmacogenetics

Pharmacogenetics is a relatively new field that combines traditional pharmaceutical sciences such as biochemistry and pharmacokinetics with an understanding of common genetic variations to predict what medications at what doses will be most effective for individuals based on their genotypes.

Each drug has its own unique metabolic profile; a specific set of enzymes responsible for catalyzing the absorption, distribution, metabolism, and excretion (ADME) of a medication. Numerous genetic variants potentially affect how much of these enzymes an individual can produce, and how efficient the enzymes will function.

Single nucleotide polymorphisms or SNPs (pronounced “snips”) are the most common type of genetic variation. Each SNP represents a change at a specific DNA base pair. A variety of SNPs influence how fast a patient will metabolize or break down certain medications. Having too little of an enzyme may decrease enzyme activity, which can cause a drug to build up in a patient’s system and result in adverse drug reactions (ADRs). Producing too much of a particular enzyme may increase enzyme activity, causing the patient’s body to excrete a medication too quickly, which may prevent the drug from ever reaching optimal therapeutic levels.

Pharmacogenetics is a relatively new field that combines traditional pharmaceutical sciences such as biochemistry and pharmacokinetics with an understanding of common genetic variations to predict what medications at what doses will be most effective for individuals based on their genotypes.

Each drug has its own unique metabolic profile; a specific set of enzymes responsible for catalyzing the absorption, distribution, metabolism, and excretion (ADME) of a medication. Numerous genetic variants potentially affect how much of these enzymes an individual can produce, and how efficient the enzymes will function.

Single nucleotide polymorphisms or SNPs (pronounced “snips”) are the most common type of genetic variation. Each SNP represents a change at a specific DNA base pair. A variety of SNPs influence how fast a patient will metabolize or break down certain medications. Having too little of an enzyme may decrease enzyme activity, which can cause a drug to build up in a patient’s system and result in adverse drug reactions (ADRs). Producing too much of a particular enzyme may increase enzyme activity, causing the patient’s body to excrete a medication too quickly, which may prevent the drug from ever reaching optimal therapeutic levels.

Informed treatment decisions based on each patient’s unique genetic make-up

Pharmacogenetics makes personalized medication more attainable by combining a patient’s genetic information with information about how specific medications are broken down in the body, allowing healthcare professionals to tailor medical treatment to the individual characteristics of each patient.

Current “one-size-fits-all” prescribing approach :

This trend toward personalized medicine represents a substantial shift in medical practice from what worked for a “typical” patient to what now works for each “individual” patient. When healthcare professionals are equipped with insight into their patients’ genetic makeup, they are able to optimize clinical outcomes and reduce adverse drug reactions.

Genetically assisted prescribing approach:

Allele – One of a pair of genes that appear at a particular location on a particular chromosome and control the same characteristic. An individual inherits two alleles for each gene, one from each parent.

Bases pairs – Two nucleotides on complimentary DNA strands. Human DNA consists of about 3 billion base pairs, and more than 99% of those are the same in all people. The order, or sequence, of these base pairs determines the information available for building and maintaining an organism.

DNA (deoxyribonucleic acid) – Contains the genetic instructions for each individual. The information in DNA is stored as a code made up of four chemical bases: adenine (A), guanine (G), cytosine (C), and thymine (T), which reside in sequence along a backbone of deoxyribose sugar and phosphates.

Chromosomes – Long stretches of DNA, which are bundled with proteins into organized structures. Chromosomes are responsible for carrying genomic material. Every individual has 22 pairs of autosomal chromosomes and two sex chromosomes.

Genes – Specified portions within the DNA, which act as instructions to make proteins, and control when and where those proteins are made. The Human Genome Project has estimated that humans have between 20,000 and 25,000 genes.

Genome – The set of all genes that specify traits in an individual.

Genotype – The composition of an individual’s genes.

Enzyme – A biological catalyst, usually a protein that speeds up the rate of a specific chemical reaction. The body contains thousands of different enzyme molecules, each specific to a particular chemical reaction.

Exons – The expressed portion of a gene, exons contain the DNA sequences that are converted to mRNA during transcription, and thus by way of the genetic code, determine the amino acid sequence in the protein product.

Messenger RNA (mRNA) – A ribonucleic acid (RNA) version of a gene that leaves the cell nucleus and moves to the cytoplasm. During protein synthesis, the ribosome, a cytoplasmic organelle, moves along the mRNA and translates each three-base triplet into the corresponding amino acid.

Nucleotide – The DNA subunit containing a base, sugar and phosphate. Nucleotides are arranged in a double-stranded configuration, forming a ladder-like structure called a double helix.

Phenotype – The physical effect that an individual’s genotype has on their body.

Single nucleotide polymorphism (SNP) – Pronounced “snip,” a single nucleotide locus with two or more naturally occurring alleles defined by a single base pair substitution. These small differences contribute to each individual’s unique physical features, including how fast medication is metabolized.

Leading medical associations support pharmacogenetic testing

When it comes to prescribing drugs and evaluating patients for potential drug interactions, pharmacogenetic testing is widely endorsed by many influential organizations.

The Dutch Pharmacogenetics Working Group has developed pharmacogenetics-based therapeutic (dose) recommendations, which are integrated into computerized systems for drug prescription and automated medication surveillance.

The American Medical Associationencourages healthcare providers to become familiar with genetic variations that can affect patients’ drug metabolism, and be able to recognize when testing should be used to inform prescribing.

The Food and Drug Administration currently recommends testing in specific instances (to determine the starting dose for warfarin, for example), and is laying the groundwork for routine testing in early phase clinical drug trials.

The American Psychiatric Association established a memorial lecture to honor David A. Mrazek. The lecture is an annual award given to individuals based on their pharmacogenomic research and their ability to relate findings to a clinical audience.

A report from the U.S. Department of Health and Human Services states: “Pharmacogenetic testing for potential adverse drug reactions (ADRs) or ineffective drug responses may reduce health care costs over the long term by diminishing the duration and severity of illness and the costs associated with ineffective treatment and avoidable ADRs.”

Individualized care for your patients based on the latest scientific advances

The G.A.P Test was developed by a team of acclaimed geneticists and is supported by a growing body of clinical research, which has been validated by the Clinical Pharmacogenetics Implementation Consortium (CPIC) and the Dutch Pharmacogenetics Working Group (DPWG).

Formed out of a partnership between the Pharmacogenomics Knowledge Base (PharmGKB) and the Pharmacogenomics Research Network, The CPIC provides physicians with prescribing guidelines for specific drugs derived from the latest pharmacogenetics research publications. Open access to these guidelines along with recommendations and a centralized listing of all known gene-drug relationships can be found at www.pharmgkb.org.

CPIC members hail from over 80 of the top research institutions, hospitals and universities including:

To learn more about the latest in pharmacogenetic research, we recommend the following studies:

Clinical Limitations of The G.A.P Test

Every patient is unique in their response to medications, and while genetics plays a major role, drug responsiveness can be based on a combination of other variables including the patient’s age, diet, other medications prescribed, and compliance in taking medications, as well as the specific disease being treated (type/stage/severity), and its co-morbidity with other diseases. This report is based solely on the specific medications and gene variants listed, and their associated interactions as published by the CPIC and DPWG and/or summarized in the drug label, and does not take all factors of the patient’s care into account. Thus, treatment decisions should be based on a global assessment of the patient, and not solely on the recommendations included in the G.A.P Test report.

G.A.P test results should always be interpreted in the context of the overall clinical picture including all co-administered medication and should NOT supersede the provider’s clinical judgement.

The individual response to medications is multifactoral. This test should not be used as the sole means of treatment decision-making and should be regarded by the ordering physician as adjunctive to the overall patient management strategy.

The G.A.P test report is based solely on the specific medications and gene variants listed in the report, and their associated interactions as published by the CPIC and DPWG and/or summarized in the drug label, and does not take all factors of the patient’s care into account.

Drug-drug and drug-gene interactions that lead to enzymatic inhibition and induction may lead to altered metabolism. Dosing should be considered in the context of other medications the patient may be taking.

In addition to concomitant medications, other variables such as age, disease, co-morbidity, organ function as well as patients’ compliance may have an impact on pharmacotherapy need to be addressed when medication is prescribed.

G.A.P test results should always be interpreted in context with the clinical picture and all co-administered medication and should NOT supersede the provider’s clinical judgement.

Scientific Limitations of The G.A.P Test

Although The G.A.P Test is amongst the most comprehensive pharmacogenetics tests on the market in terms of coverage, not all genotypes/haplotypes (including copy number variations and novel haplotypes containing rare or yet to be discovered mutations), that have been reported in the literature are covered by The G.a.p Test.

The following is a list of haplotypes and genotypes that are covered by The G.a.p Test:

CYP2C19: *1, *2, *3, *4, *4B, *8, and *17.

CYP2C9: *1, *2, *3, *5, *6, *8, *12, and *14.

CYP2D6: *1, *3, *4, *6, *7, *8, *9, *14A, *29, and *41.

DPYD: *1, *2A, *13, rs2297595, rs56293913, and rs67376798.

Factor V Leiden: rs6025.

SLCO1B1: rs4149056.

TPMT: *1, *2, *3A, *3B, *3C, and *8.

VKORC1: rs9923231, and rs9934438.

The test method was designed assuming that genetic markers and genes follow classical Mendelian genetics, in that there are only two copies of each genetic marker or gene within a genome. The G.A.P test method examines single nucleotide polymorphisms, and does not include reference genetic markers for quantification. As a result of this, the test is not able to accurately and consistently predict gene copy number, which has been shown in some cases to impact drug metabolism.

In some rare instances, genes/genetic markers may be duplicated in such a way that the duplications are non-functional. These are called pseudogenes. As is the case for all genotyping platforms, because The G.A.P Test only examines single nucleotide polymorphisms and is not able to examine whether an enzyme is produced from that gene, we are unable to differentiate between functional genes and pseudogenes. Similarly, patients may have novel, uncharacterized or rare genetic variations located near SNPs that are covered by The G.A.P Test that interfere with The G.A.P Test assay. In these rare instances, the accuracy of the recommendations provided in the test report may be impacted.

The test method examines single nucleotide polymorphisms, of which there are 4 biological possibilities for any one SNP position: A, C, G or T. The G.A.P test was designed considering the two most clinically relevant nucleotides for each one of the SNPs included in the test. Therefore, although rare, it is possible that an individual may carry a SNP allele that is not considered in the test, possibly resulting in no clinically validated recommendation being made for that gene or medication.

Recommendations for medications are based on CPIC and DWPG guidelines, and/or summarized in the drug label itself. Recommendations are based on defined genetic haplotypes and knowledge of how particular SNPs affect the function of the gene. Haplotypes consist of a group of SNP alleles that are linked to a change in drug metabolism. Given the comprehensive nature of The G.A.P Test, novel haplotypes will be discovered through routine testing. In such cases, a functional prediction will be made based on the known functions of the SNPs that make up each novel haplotype.

CPIC and DWPG recommendations are based on defined genetic haplotypes, and it is common for haplotypes to change due to new research or clinical findings due to the evolving nature of clinical pharmacogenomics. In some instances, previously defined haplotypes may be reclassified as completely new haplotypes with new medication recommendations. Firefly Diagnostics will update our recommendation guidelines based on haplotype changes on a monthly basis, however this is a limitation for most diagnostic genetic testing systems.

III. Interfering Substances

Purified DNA and primers should be resuspended in ultrapure water instead of TE (Tris-EDTA buffer) as the EDTA may chelate the magnesium needed for optimal PCR performance.

Any resin carry-over due to improper height adjustment of spotting pins may affect the quality of data obtained from the mass spectrometer.

In some rare occasions, non-specific extension products may be observed in the spectra due to homology between extension primers and either amplification/extension primers or amplification products. Validation studies will eliminate SNPs that consistently produce non-specific extension products, however it is possible that these “water” calls are occasionally observed but will not impact the ability of the lab staff to analyze the results of the test.

Stay updated on the rapidly evolving field of pharmacogenetics

Every day new research is conducted and additional guidelines are published on how to integrate this science into clinical practice.